XBP1 is essential for survival under hypoxic conditions and is required for tumor growth
XBP1 is essential for survival under hypoxic conditions and is required for tumor growth
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DOI：
10.1158/0008-5472.can-04-1606
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Koong, AC
中科院分区：
文献类型：
--
作者：
Romero-Ramirez, L;Cao, HB;Koong, AC
实体瘤内的缺氧是抗癌治疗后结果的主要决定因素。缺氧过程中的基因表达变化的分析表明，未折叠蛋白反应基因是最稳健的诱导基因组之一。在这项研究中，我们研究了缺氧调节的X-box结合蛋白（XBP 1），一个主要的转录调节未折叠的蛋白质反应。缺氧在转录水平诱导XBP 1并激活其mRNA的剪接，导致激活的XBP 1蛋白水平增加。暴露于缺氧后，细胞凋亡增加，克隆存活减少，在XBP 1缺陷细胞。由于这些移植的肿瘤细胞在缺氧微环境中存活的能力降低，XBP 1的缺失严重抑制了肿瘤生长。综上所述，这些研究直接暗示了XBP 1是缺氧应激和肿瘤生长的重要存活因子。
Hypoxia within solid tumors is a major determinant of outcome after anticancer therapy. Analysis of gene expression changes during hypoxia indicated that unfolded protein response genes were one of the most robustly induced groups of genes. In this study, we investigated the hypoxic regulation of X-box binding protein (XBP1), a major transcriptional regulator of the unfolded protein response. Hypoxia induced XBP1 at the transcriptional level and activated splicing of its mRNA, resulting in increased levels of activated XBP1 protein. After exposure to hypoxia, apoptosis increased and clonogenic survival decreased in XBP1-deficient cells. Loss of XBP1 severely inhibited tumor growth due to a reduced capacity for these transplanted tumor cells to survive in a hypoxic micro-environment. Taken together, these studies directly implicate XBP1 as an essential survival factor for hypoxic stress and tumor growth.